4-phenyl-2-(3-pyridyl)-thiazole carboxamides

ABSTRACT

A broad class of thiazole derivatives, including certain novel 2-(3-pyridyl)thiazoles, are useful as anti-inflammatory agents.

[ 4-PHENYL-2-(3-PYRIDYL)-THIAZOLE CARBOXAMIDES [75] Inventors: Zaven S. Ariyan, Woodbury, Conn.;

William A. Harrison, Guelph, Ontario, Canada [73] Assignees: Uniroyal, Inc., New York, N.Y.;

Uniroyal Ltd., Montreal, Quebec, Canada [22] Filed: June 21, 1972 21 Appl.No.:26 4,817

[52] US. Cl. 260/294.8 D, 260/2471, 260/2948 E,

424/248, 424/263 [51] Int. Cl C07d 31/50 [58] Field of Search 260/294.8 D

[56] References Cited UNITED STATES PATENTS 3,705,153 12/1972 Kaneko ct a1 260/2948 D OTHER PUBLICATlONS Burger, Medicinal Chemistry, Third Edition, Part Two, Pages 956-958, Wiley lnterscience Publishers. RS403B8 C2 1970.

Primary ExaminerAlan L. Rotman Attorney, Agent, or Firm-Bruce F. Jacobs, Esq.

[5 7] ABSTRACT A broad class of thiazole derivatives, including certain novel 2-(3-pyridyl)thiazoles, are useful as antiinflammatory agents.

4 Claims, No Drawings 1 4-PHENYL-2-(3-PYRIDYL)-THIAZOLE CARBOXAMIDES CROSS REFERENCE TO RELATED APPLICATIONS This application is related to, and incorporates by reference, the application of Harrison et al., Ser. No. 140,571, filed on May 5, 1971, which discloses methods for preparing many of the thiazole derivatives of the present invention.

BACKGROUND OF THE INVENTION 1. Field of the Invention The invention relates to thiazole derivatives, some of which are novel compounds, which are useful as antiinflammatory agents, i.e., they prevent and/or inhibit the formation of granuloma tissue in animals. Accordingly, the invention is, in one aspect thereof, a method of preventing and/or inhibiting the formation of granuloma tissue in animal subjects. In a second aspect, the invention is a class of pharmaceutical compositions containing the present thiazole derivatives. In a third aspect, the invention is a class of novel compounds.

2. Description of the Prior Art Thiazole derivatives, including numerous pyridylthiazoles are known.

The French patent application FMO8423, for example, discloses certain thiazole derivatives as having anti-inflammatory activity. These compounds are structurally dissimilar to the compounds of the present invention in that they are all substituted in the pyridyl ring by a group such as =0, OR or SR. The compounds of the present invention, on the other band, do not contain any such groups in the pyridyl rings thereof.

Dutch patent application 70/07029 discloses a group of 2-(3-pyridyl)thiazoleacetic acid derivatives as having anti-inflammatory activity.

The application of Harrison et al., noted above, discloses a broad class of 2-(3-pyridyl)thiazoles and methods for preparing same.

According to the application of Harrison et a1., 2-(3- pyridyl)thiazoles are prepared by well known methods of thiazole synthesis. Thus, as described in Harrison et al., a thioamide of the formula:

is reacted with an a-halocarbonyl compound of the for mula:

in the presence of a solvent such as alcohol with heating, followed by basification to form a compound of the formula:

r a t Pyr--- D Hal-- a monoor di-substituted carbamoyl group and Hal is a halogen.

SUMMARY OF THE INVENTION The invention provides a safe and effective method of preventing and inhibiting the formation of granuloma tissue in an animal subject. This is achieved by administering to an animal subject a therapeutically effective amount of at least one compound selected from a very large group of 2-(3-pyridyl)thiazoles, some of which are known and some of which are novel. Generally, the amount administered will be from about 0.1 to mg/kg/day of body weight. preferably from about 10 to 50 mg/kg/day. In humans, the amount will be from about 0.1 to 2 mg/kg/day, preferably from about 0.25 to 1.0 mg/kg/day.

The invention further provides a new class of 2(3- pyridyl)thiazoles with are effective as anti inflammatory agents, as well as pharmaceutical compositions comprising both the known and novel thiazole derivatives.

The 2-(3-pyridyl)thiazoles which are among those used in the present methods are those having the formulae:

III

1v--- V I \N R (A) wherein R is a. hydrogen;

b. COOR,, wherein R is an alkyl group of up to six carbon atoms, propynyl, cyclohexyl or methoxyethyl;

c. CONR R wherein R is hydrogen and R is hydro gen, an alkyl group of up to four carbon atoms,

tolyl, pyridyl, or cyclohexyl; or wherein R and R are independently selected from the group consisting of alkyl groups of up to three carbon atoms and phenyl; or wherein R and R together with the nitrogen atom to which they are bound, form a pyrrolidino or 2,6-dimethylmorpholino group; or

d SP'NNHCOK I S/ cor wherein R is hydrogen or an alkyl group of up to three carbon atoms and R is an alkyl group of up to three carbon atoms; and pharmaceutically acceptable acid addition salts thereof.

The pharmaceutical compositions according to the invention comprise, in combination, a therapeutically effective amount of at least one of the above-described thiazole derivatives and a pharmaceutically acceptable carrier and/or diluent therefor.

For example, in the case of a tablet, the composition will comprise, in addition to the active ingredient, fillers, binders and diluents such as lactose, methylcellulose, talc, gum tragacanth, gum acacia, agar, polyvinylpyrrolidone, stearic acid, and/or corn starch, etc. In the case of a liquid suspension for oral administration, the composition will comprise, in addition to the active in gredient, a filler such as sodium carboxymethylcellulose and/or syrup, e.g., a glycerine-based syrup. In

the case of a parenteral solution or suspension, the composition will comprise, in addition to the active ingredient, a suitable solvent or other liquid such as a saline solution. In the case of a topical ointment, the composition will comprise, in addition to the active ingredient, a vehicle such as petroleum jelly or hydrophilic petrolatum.

The most preferred compound from among those of the formula (A) is N,N,4-trimethyl-2-(3-pyridyl)-5- thiazolecarboxamide, i.e., the compound wherein R is CON(CH R is methyl, and R" through R" are hydrogen. This compound in the rat (at a dose of 200 mg/kg) produces a reduction of 41% in carrageenininduced edema.

Another preferred compound is 4-ethyl-2-(3- pyridyl)-thiazole, i.e., the compound wherein R is hydrogen, R is ethyl and R" through R" are hydrogen. This compound in the rat (at a dose of 200 mg/kg) produces a reduction of 33% in carrageenin-induced edema.

The most preferred compound from among those of the formula (B) is N-isopropyl-4-phenyl-2-(3-pyridyl)- S-thiazolecarboxamide, i.e., the compound wherein R is hydrogen and R is -CH(CH This compound in the rat (at a dose of 200 mg/Kg) produces a reduction of 42% in carrageenin-induced edema. The preferred compounds also include their pharmaceutically acceptable acid addition salts.

The novel compounds of the invention are those of the formula (A) wherein R is C(CH )=NNHCONH R is CH and R" through R" are hydrogen; and those 11 NHZ l R S V IV R N wherein R, R, R, R', R" and R" are as defined above and Hal is a halogen to form the hydrohalide salt of the 2-(3-pyridyl)-thiazole of the formula (A):

The free base is obtained from the hydrohalide salt by basification with an alkali such as ammonium hydroxide, an alkali metal hydroxide, sodium bicarbonate, etc. Alternatively, one may use excess thioamide in the reaction to neutralize the hydrogen chloride produced. Under these conditions the reaction yields the free base directly and the unreacted thioamide can be recovered from its hydrohalide salt by treatment with a base such as ammonium hydroxide, an alkali metal hydroxide or sodium bicarbonate.

A method for preparing the compounds of the formula (B) is the reaction sequence which comprises reacting an a-halocarbonyl compound of the formula:

Hal-CH-CON CON a of the formula (B) wherein R and R are both methyl or ethyl, or R is hydrogen and R is methyl or isopropyl; and the hydrochlorides thereof.

DETAILED DESCRIPTION 0 C-RI and a thioamide of the formula:

The free base is obtained in the same manner as de scribed above.

The actual preparation of the 2-(3-pyridyl)thiazole derivatives consists of mixing the a-halocarbonyl compound with the thioamide (excess thioamide may be used) in the presence of a suitable polar solvent such as dimethylformamide or a lower alkanol and heating the mixture to about 60 to C for 2 to l0 hours, followed by basification. The 2-(3-pyridyl)thiazole formed in the reaction is then isolated using conventional techniques.

When the required a-halocarbonyl compound is not readily available, it may be convenient to prepare another pyridylthiazole derivative and convert it to the desired product. For example, ethyl a-chlorobenzoylacetate and thionicotinamide can be reacted to yield ethyl-4-phenyl-2-( 3-pyridyl )5-thiazolecarboxylate,

which can be used as an intermediate for preparation pyridyl)-5-thiazolecarboxamide.

Another example is the semicarbazone of methyl-4- methyl-2-(3-pyridyl)-5-thiazolyl ketone (formula (A) wherein R is C(CH )=NNHCONl-l R is CH and R, R', R and R" are each H). The ketone can be prepared from thionicotinamide and 3-chloro-2,4- pentanedione by the methods described above. Reac- 6 hydrochloride) removed by filtration. The filtrate was washed three times with cold sodium hydroxide solution (50, and 25 ml. portions) and extracted twice with dilute hydrochloric acid (a total of I25 m|.. prepared by dilution of nil. of 37% acid). The acid extracts were made basic with aqueous ammonia and extracted three times with chloroform 100, and 50 ml. portions). The chloroform extracts were dried with anhydrous sodium sulfate, filtered and evaporated. The

tion of the ketone with semicarbazide hydrochloride in 10 residual pale yellow liquid solidified when cooled and the presence of sodium acetate (a well known method of making semicarbazones) yields the desired product.

As previously stated, the application of Harrison et al. discloses and exemplifies the preparation of many of scratched with a glass rod. After it was dried to constant weight under vacuum, the solid, N,N.4-trimethyl- 2-(3-pyridyl)-5-thiazolecarboxamide, weighed 36.4 g. (73% yield based on 2-chloro-N,N-

the compounds of the present invention using the IS dimethylacetoacetamide) and melted at 63-66C. On

above-described methods. For the sake of convenience and completeness, however, there follow working examples showing the preparation of some of the present compounds usisng the same methods. It will be understorage the product slowly changed to another crystal form which melted at 9()-93C. Recrystallization from toluene-ligroin or ethyl acetate-hexane gave crystals melting at 6768C or Xi-95C, depending on which stood, of course, that the methods are also applicable 20 crystal form was used to seed the solution.

to all the compounds of the present invention.

EXAMPLE 1 Preparation of N,N,4-trimethyl-2-(3-pyridyl)-5-thiazolecarboxamide 25 Thionicotinamide (55.2 g., 0.40 mole), 2-chloro- N,N-dimethylacetoacetamide (32.7 g., 0.20 mole) and methanol (200 ml.) were heated under reflux with stirring for four hours. The solvent was evaporated under reduced pressure, toluene (300 ml.) added to the residue and the insoluble solids (mostly thionicotinamide EXAMPLES 2-26 T A B L E I 2- g 3-PYRIDYL1THIAZOLES R NI I RI III R s R RIV R Example C I p c R R Yield Percent* M.P.' 0. Salt:

1 1 -CON(CH3)2 -01: 73 67-68, 93-95 2 2 CONH2 --Cl-I 54 204-207 HCl 241-2c1 3 3 -11 -c 11 37 33-35 HCl 166-8 4 4 -C=NNHCONH2 -ca 222-224 5 5 CON(C2H5)2 -ca s9 (62) 39-41 u so 148-50 6 6 -cooca czca -ca 2 2 124-125 7 7 -CONHC H (o-CH -CONHC6H4(0 -CH3) 183-187 8 s -coo@ -r;1i 15 63-64 9 9 -C()O(Ill Cll 0Cll- Cll 7O 76'78 10 111 11000 11.; -cooc u I 11 69-71 1.1, 11 41006 11 cu 66 77-79 12 12 -cor 1(cu(cu cli 61 (43) 09-70 1) l3 -CONll((2lI Cll -Cll 52 (36) tow-1.10

,011 14 14 -comicn -cu es 46 144-145 15 15 -CONHCH2CH(CH3)2 -cn 62 43 111-112 fzzim lc. are R RI Yield Percent=- rm. c. M w (min l6 l6 -COOCH(Cl-l )Cl-l -CH(CH -CH3 24 Oil on 17 17 -co 3 -cr 42 29 135-136 18 18 CON -Cl-l 55 (39 Oil H 19 19 -CON/ 2 -cri a1 22 85-86 2o 20 -CONH(2-pyridyl) -crr 29 20 198-199 21 21 -CONH-(3pyridyl) -'cn 77 (54 157-158 22 22 -C00CH(CH3)2 -(;H3 19 89-9 HCl 205-7d 23 23 -H -CONHCH3 65 (46) 113-115 H2504 181-3 24 24 -cor1 ca 66 46 75-77 2 5 25 -coN1-1-@ -Cl-l 69 as 63-64 26 26 -C0N(CH3)2 -c r-i v 94 (61) 011 RII, RIII, RIV and RV are all hydrogen except in compound 11 wherein RlIvI is CH3 *The yields given for compounds 1, 3, 8, 9, 10, ll,

appropriate thioamide and a-halocarbonyl compound as described in detail in Example 1. was made by reacting methyl 4-methyl-2- (3-pyridyl)5 thiazolyl ketone with semicarbazide and sodium acetate in ethanol. The ketone was made pentanedione by the method represented by Example 1 16 and 22 are for their direct synthesis from the Compound 4 hydrochloride by reacting thionicotinamide with 3-chloro-2 4- The overall yield is given. were made indirectly from thiazolecarboxylic acids as described in detail in Example 27.

The other compounds The firs I:

figure is the yield based on the intermediate acid and the figure in parentheses is the overall yield The following Example describes a multi-step synthesis of a 2-(3-pyridyl)thiazole of the formula (B).

EXAMPLE 27 Preparation of N,N-dimethyl-4-phenyl-2-( 3-pyridyl )-5- thiazolecarboxamide Thionicotinamide (69 g., 0.50 mole), ethyl a-chlorobenzoylacetate (114 g., 0.50 mole) and absolute ethanol (600 ml.) were heated under reflux for 6 hours. Three hours after the reaction was started, dropwise addition of triethylamine (50.5 g., 0.50 mole) was begun. Half of the amine was added during the fourth hour of heating and the rest during the fifth and sixth hours. The reaction mixture was cooled and the solid based on the thioamide and original q -h alocarbonyl compound.

A slurry of the acid (56.4 g., 0.20 mole) in toluene (500 ml.) was treated with thionyl chloride (42 g., 0.35 mole) and heated with stirring at 6070C for 4 hours. The reaction mixture was cooled and the solid, crude 4-phenyl-2-'( 3-pyridyl )-5-thiazolecarbonyl chloride hydrochloride, collected by filtration and washed with toluene. The solid was then added in portions to a cold, stirred mixture of toluene (500 ml.) and 40% aqueous dimethylamine ml.). The reaction mixture was stirred at room temperature for about 2 hours, the layers were separated, and the toluene layer washed with water and extracted with dilute hydrochloric acid (50 ml. of 37% acid diluted to 250 ml.). When the acid extract was made basic with aqueous ammonia, an oil precipitated which subsequently solidified. The dried product, N,N-dimethyl-4-phenyl-2-(3-pyridyl)-5- thiazolecarboxamide, weighed 58 g. (94% yield from the acid of 68% overall) and melted at 119 122C. After recrystallization from ethyl acetate the product melted at l2l-l23C.

Treatment of a cold acetone solution of the product with a slight excess of 37% hydrochloric acid gave a precipitate of the hydrochloride, m.p. 2l2217C (dependent on rate of heating).

The following Examples 27-3 l, as set forth in Table ll are directed to the preparation of other 2-(3- pyridyl)thiazoles of the formula (B).

. TABLE. 11

Z (3 PYRIDYL) THIAZOLES I CON/R7 Example Q51 R7 R8 Yieldl 14.1. C.

27 27 -cu -c11 94 (6!) 121-123 28* 28* -CH -CH as 58 212-217 29 29 -c n -c 11 75 54 73-75 3o -n CH(CH3)2 s3 (60) 122-125 31 31 -n -cn 4s 32 190-192 *h d'zeemar dap W n 2% The compounds of the present invention have pharmaceutical activity as anti-inflammatory agents, effec tive in the prevention and inhibition of granuloma tissue formation. The activity is demonstrated by a test which involves the diminution of experimental edema induced in the hind paw of the rat by the injection of carrageenin. This test is a standard procedure which is well known in the pharmaceutical art.

The procedure used for measuring the inhibition of carrageenin-induced edema is a modification of the method of Winter et al., Proc. Soc. Exptl. Biol. Med. 1 l l: 544 (I962). The device used for measurement of the paw volume is an adaptation of the water displacement procedure described by Adamkiewicz et al., Can. J. Biochem. Physiol. 33: 332 (1955). The present compounds were studied for their effectiveness in preventing the edema caused by the intraplantar injection of 0.05 ml. of a sterile 1.0% solution of carrageenin. The present compounds were administered orally one hour prior to the injection of the carrageenin into the left hind paw of rats. At peak swelling time (3 hours) the volume of edema was calculated by differential paw volume.

We have found that many of the compounds produced significant inhibition of induced edema in rats at a dose rate of 200 mg/kg.

Table III lists the compounds of the formula (A) which exhibit reduction in edema in the hind paw of the rat.

TABLE Ill 7? reduction of induced edema Cpd. No.

TABLE III Continued Reduction in Edema at 200 mg/kg Compounds of Formula (A) Cpd. No. reduction of induced edema Oooo\| l2 l3 l4 l5 l6 l7 l8 I9 20 21 22 23 24 25 26 Table IV lists the compounds of the formula (B) which exhibit reduction in edema in the hind paw of the rat.

TABLE IV Reduction in Edema at 200 mg/kg Compounds of Formula (B) Cpd No. 7( Reduction Edema at 200 mg/kg hydrochloride of Compound 27 As can be readily seen from the foregoing Tables Ill and IV, all of the compounds of the present invention are effective in reducing induced. edema by at least 20% in the rat at a dose of 200 mg/kg.

The compounds numbered 1, 3, 4, 8, 14-21 and 29 (see Tables II and IV) were selected for further study to determine the ED in edema reduction. In this test, a group of normal rats was injected with carrageein to induce edema. Then the rats were treated with varying amounts of the above-described thirteen compounds, and the ED was determined.

The procedure used for measuring the inhibition of carrageenin-induced edema is the above-described modification of the method of Winter et al., Proc. Soc. Exptl. Biol. Med. 1 1 1: 544 (1962). The device used for measurement of the paw volume is an adaptation of the water displacement procedure described by Adamkiewicz et al., Can. J. Biochem. Physiol. 33: 322 (1955). The above compounds were studied for their effectiveness in preventing the edema caused by the intraplantar injection of 0.05 ml. of a sterile 1.0% solution of carrageenin. Compounds were administered orally 1 hour prior to the injection of the carrageenin into the left hind paw of rats. At peak swelling time (3 hours) the volume of edema was calculated by differential paw volumes. The ED value was obtained for each compound and is defined as that dose which reduced edema formation by 25% or more compared with the mean control response (parallel run) in 50% of the animals.

The results of this test are given in Table V.

Compounds 1, 3 and 8 were then studied to determine the ED in adrenalectomized rats using the same range of doses as in the previous test.

The method used was identical to that described TABLE VI ED, vs. Carrageenin Assay in Adrenalectomized Rats Com- Dose (mg/kg) ED mg/kg Confidence pound No. Limits From Tables V and VI, it can be seen that Compound 1 has a lower ED than all the other compounds in adrenalectomized rats as well as in normal rats.

The LD of each of Compounds 1, 3 and 8 was determined and from the value of each, the therapeutic index was calculated. The therapeutic index is defined as the LD divided by the ED in the carrageenin assay. The results are given below in Table VII:

TABLE VII THERAPEUTIC INDEX Com- LD (mg/kg) Therapeutic pound No. 48 hrs. and 5 days ED (mg/kg) Index int. Pharmacodyn., 175: 186, 1969. This method utilizes the carrageenin-induced paw edema and the drug is injected locally simultaneously with the irritant substance, carrageenin, into the plantar surface of the hind paw of rats. Male rats weighing between and grams, fasted for 18 hours prior to use were employed in this study. The test compounds were added directly to the 1% carrageenin solution and injected in a volume of 0.5 ml. into the plantar tissue of the left hind paw. A group of control animals received carrageenin only. Three hours later the edema was measured. Antiinflammatory or irritant effect was calculated as the percent increase or decrease in edema between the control groups and the treated groups. Ten rats were used per group. The calculated ED was based on the number of animals in each group which showed an increase or decrease of at least 25% from the mean control values.

TABLE VIII Local vs. Systemic Edema [ED vs. Carrageenin] Com- Dose (mg/paw) ED (Confidence Limits) pound No.

1 1, 2, 4, 8 8 mg/paw 3 1, 2, 4. 8 1.23 mg/paw (0.89-1.68)

In the cotton pellet granuloma test, Compound 1 has an ED of 8 mg/kg. (Confidence Limit 5.4 12.8.)

In this test, the inhibition of granuloma formation was determined by a modification of the method of Meier et al., Experientia 6: 469 (1950). Essentially, the test consists of subcutaneously implanting a sterile cotton disc into rats with the concomitant oral administration of the test compounds twice daily for 4 days. Re-

moval of the pellets along with the granuloma formation after five days was performed and the increment in dry weight was considered as the measure of granuloma formation. Based on several studies, a 40% reduction in granuloma formation is considered significant.

Thus, a dose of 8 mg/kg is sufficient to cause a 40% reduction in granuloma formation in 50% of the test animals.

The adjuvant-induced arthritis test was also conducted in rats using Compound 1. This test requires one month (from O to day 31). In the first 17 days (17), the disease is in a developing stage, while for the remainder of the month (18-31 the disease is fully developed. The results of this test, given in terms of percent reduction of swelling in the hind paw of the rat are shown in Table IX.

The method is essentially that of Newbould, Brit. J. Pharmacol. 21: 127, 1963. The test compound was studied in the developing arthritic state and in the established arthritic state. Separate groups of 12 rats were administered the compound orally using methylcellulose as the vehicle. In the study on the developing disease, administration of the test compound begins on day l and on day 2 each animal is injected with 0.05 ml/kg of a 0.5% suspension of heat-killed Mycobacterium tuberculosis into the plantar surface of the left hind paw. Foot volumes were measured by a water displacement device on the day of administration of the Mycobacterium and again on days 3, and 17. The test compound was administered once daily. Body weights were recorded daily and the animals were examined for the spread of the inflammation and the degree of secondary lesions observed and scored as mild, moderate, or severe. For study in the established disease, another group of rats are injected with the Mycobacterium and foot volumes are measured and after days are again measured and administration of the test compounds begin and continues for 1 1 days. Foot volume measurements are repeated on day 27 and day 31. The extent of the spread of the inflammation and the degree of lesions are recorded daily as are the body weights. The effect of the test compound is measured by the percentage reduction in left hind paw volumes as compared to the hind paw volumes of the control groups.

TABLE IX ADJUVANT-INDUCED ARTHRITIS TEST IN RATS Reduction in Swelling Hind Paw DAY Developing Disease Developed Disease COMPOUND l 50 mg/kg adminstered in the form of tablets, pills. capsules. or in the form of a suspension. The compounds may also be administered parenterally in the form of an injectable solution or suspension. The compounds or compositions thereof may also be administered topically. in the form of an ointment or rectally, in the form of a suppos itory.

When orally administering the compounds or compositions, use can be made of a tablet, pill or capsule consisting entirely of the desired compound. although ordi narily, a composition comprising an effective amount of the compound and varying amounts of one or more physiologically inert materials such as carriers, vehicles, binders and the like will be used. Additionally, the compounds may be orally administered in the form of a suspension thereof in a suitable vehicle such as a syrup.

When parenterally administering the compounds or compositions, use may be made of a parenteral solution or suspension of the compound in a suitable solvent or suspension medium.

The compounds of the present invention may also be administered rectally in the form of a suppository comprising an effective amount of the desired compound and a suitable vehicle such as petroleum jelly.

Finally, the compounds of the present invention may be applied topically in the form of an ointment, salve, cream or lotion comprising an effective amount of the desired compound and a suitable vehicle such as petroleum jelly, etc.

The following examples are specific formulations of the compositions according to the invention.

EXAMPLE 32.

Tablets may be prepared by the compression of a wet granulation containing the following:

Dosage: l Tablet 3 times a day.

EXAMPLE 334 A liquid suspension for oral administration may be prepared in the following formulation:

Ingredients In each 5 cc Compound NO. 1 30 mg Sodium carboxymethylcellulose 5 mg Syrup USP q.s. to 5 cc Dosage: l teaspoonful (5 cc) every 3 to 4 hours.

EXAMPLE 34 Dry filled capsules (DEC) consisting of two sections of hard gelatin may be prepared from the following formulation:

Ingredients In each Compound No. l 30 mg Lactose USP q.s.

Dosage: 1 capsule three times a day.

EXAMPLE 35 An ointment for topical use may be prepared using the following formulation:

Ingredients In each Compound No. l gm Hydrophilic petrolatum USP q.s. 100 gm Dosage: To be applied to inflamed skin areas as needed.

n EXAMPLE 36 H A parenteral suspension for intra-muscular administration may be prepared in the following formulation:

Ingredients Compound No. 1 mg isotonic solution (0.85% saline) 5 cc Surfactant (a l% solution of polysorbate 80 USP) Variations and modifications can, of course, be made without departing from the spirit and scope of the invention.

Having thus described our invention, what we desire to claim and protect by Letters patent is:

1. A compound of the formula: 

1. A COMPOUND OF THE FORMULA:
 2. A compound as claimed in claim 1, wherein R7 and R8 are both -C2H5.
 3. A compound as claimed in claim 1, wherein R7 is hydrogen and R8 is -CH(CH3)2.
 4. A compound as claimed in claim 1, wherein R7 and R8 are both -CH3 and the hydrochloride thereof. 